SGCG

protein-coding

sarcoglycan gamma

Gene summary

This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

Previous symbols:

DMDA1
MAM
LGMD2C

MANE transcript

NM_000231.3

Inheritance

ClinVar variants

P:120U:185B:124

Top phenotype

Muscular dystrophy, limb-girdle, limb-girdle, autosomal recessive, 5

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr13:23,180,979-23,325,162

External References & Databases

Ensembl (ENSG00000102683)

Transcript & Mutation Effects

hg38 • Region Span ~144.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophy type 2CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009677

Submitter: Myriad Women's Health

autosomal recessive limb-girdle muscular dystrophy type 2CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009677

Submitter: Ambry Genetics

autosomal recessive limb-girdle muscular dystrophy type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009677

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: PanelApp Australia

autosomal recessive limb-girdle muscular dystrophy type 2CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009677

Submitter: Natera

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

SGCG was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 1995 (Noguchi et al., PMID: 7481775). The original disease nomenclature used was LGMD2C, which was later transitioned to LGMDR5. At least 75 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, etc) have been reported in humans according to HGMD. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least eight probands in four publications (PMIDs: 8923014, 7481775, 8968757, 27708273). Variants in this gene segregated with disease in over fifty additional family members. SGCG has many recognized founder variants passed down through smaller isolated populations, some being the North African variant 525delT and the Roma variant among others. SGCG also is prone to large exonic deletions, most prominently the deletion of Exon 6 but others have previously been reported. Many more probands and evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is protein loss of function, with loss of gamma-sarcoglycan resulting in a corresponding loss of the other sarcoglycans and destabilization of the Dystrophin-Associated Protein Complex from the sarcolemma. This gene-disease association is supported by animal models, expression studies, functional assays, and a functional rescue. Protein interactions and having the same biochemical function as the other sarcoglycans associated with LGMD provides strong evidence, as well as the primary expression in skeletal muscle. Mouse models of disrupted SGCG function consistently recapitulate the human LGMD phenotype. Additionally, the introduction of full length SGCG cDNA via a viral construct rescued the disease phenotype observed in the mouse. In summary, SGCG is definitively associated with autosomal recessive limb-girdle muscular dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on April 14, 2020 (SOP Version 7). This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.

autosomal recessive limb-girdle muscular dystrophy type 2CSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009677

Submitter: Orphanet

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, limb-girdle, autosomal recessive, 5AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 1303286; 7481775; 8923014; 8968757; 10507732; 10720277; 16832103; 18285821

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGCG variants in ClinVar

11 Conditions Cataloged

Autosomal recessive limb-girdle muscular dystrophy type 2CTotal: 481

not providedTotal: 124

not specifiedTotal: 42

Inborn genetic diseasesTotal: 26

SGCG-related disorderTotal: 23

Autosomal recessive limb-girdle muscular dystrophyTotal: 20

SarcoglycanopathyTotal: 15

Abnormality of the musculatureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000231.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			14 clinvar	115 clinvar	1 clinvar	130
missense	2 clinvar	9 clinvar	168 clinvar	7 clinvar	1 clinvar	187
nonsense	7 clinvar	18 clinvar	2 clinvar			27
start loss						0
frameshift	29 clinvar	25 clinvar				54
splice donor/acceptor (+/-2bp)	9 clinvar	21 clinvar	1 clinvar			31
Total	47	73	185	122	2	429

Highest pathogenic variant AF is 0.00009232157

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000231.3	RefSeq	NP_000222.2	7	MANE Select
ENST00000218867.4	Ensembl	ENSP00000218867.3	7	MANE Select
NM_001378244.1	RefSeq	NP_001365173.1	8	Standard
NM_001378245.1	RefSeq	NP_001365174.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Dilated cardiomyopathy (DCM) - Homo sapiens (human)
Viral myocarditis - Homo sapiens (human)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
Arrhythmogenic Right Ventricular Cardiomyopathy

Biological Process

muscle organ development
cardiac muscle tissue development
heart contraction

Molecular Function

protein binding

Cellular Component

nucleoplasm
cytoplasm
cytoskeleton
plasma membrane
sarcoglycan complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000218867
Coding exons: 7
Length: 144214
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125748
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.134	168	163	1.03	0.00000874	1881
Missense (PolyPhen)		64	65.214	0.98139		773
Synonymous	-1.14	73	61.6	1.18	0.00000359	562
Loss of Function	1.44	9	15.0	0.600	7.03e-7	180

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.;

Recessive Scores

pRec: 0.363

Intolerance Scores

LoFtool: 0.314
RVIS EVS: -0.14
RVIS percentile EVS: 43.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0893

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium